ABSTRACT The misuse of ionizing radiation or nuclear devices as weapons of terrorism has been recognized as a major U.S. public health threat. The greatest risk to these victims of radiation exposure is the hematopoietic acute radiation syndrome (H-ARS), which results in life-threatening complications such as infections and refractory bleeding. Specific therapies directed at H-ARS to accelerate hematopoietic regeneration following radiation injury have been few. Since marrow endothelial cells can govern hematologic recovery after irradiation without homing to the bone marrow, endothelial cells can mediate their radioprotective effects through elaboration of hematopoietic cytokines or soluble factors. Another mechanism of cellular communication is through transfer of proteins and nucleic materials via secretion of extracellular vesicles (EVs). EVs range in size from 100-250 nm and bear both nucleic acids and proteins that have potential to regulate neighboring cells. We hypothesize that ECs exert their regenerative effects through EVs. We have shown that treatment of irradiated hematopoietic stem/progenitor cells with either syngeneic or allogeneic EVs from genetically distinct mice results in comparable expansion of the stem cell pool, suggesting they could be immunologically tolerant. Compared to control mice treated with granulocyte colony stimulating factor (G-CSF), it is possible that EVs are at least comparable and are likely superior to G-CSF for prolonging survival after lethal-dose irradiation. Our overriding goal is to demonstrate the radiotherapeutic capacity of EVs. In doing so, we will develop a cellular-based therapy for H-ARS with potential for off-the-shelf delivery to victims in the setting of a mass casualty disaster.